Purpose of review: The systematic analysis of the major candidate genes in autosomal dominant hypercholesterolemia (ADH) and the use of next-generation sequencing (NGS) technology have made possible the discovery of several rare gene variants whose pathogenic effect in most cases remains poorly defined.
Recent findings: One major advance in the field has been the adoption of a set of international guidelines for the assignment of pathogenicity to low-density lipoprotein receptor (LDLR) gene variants based on the use of softwares, complemented with data available from literature and public databases. The clinical impact of several novel rare variants in LDLR, APOB, PCSK9, APOE genes have been reported in large studies describing patients with ADH found to be homozygotes/compound heterozygotes, double heterozygotes, or simple heterozygotes. In-vitro functional studies have been conducted to clarify the effect of some rare ApoB variants on LDL binding to LDLR and the impact of a rare ApoE variant on the uptake of VLDL and LDL by hepatocytes.
Summary: The update of the ADH gene variants database and the classification of variants in categories of pathogenicity is a major advance in the understanding the pathophysiology of ADH and in the management of this disorder. The studies of molecularly characterized patients with ADH have emphasized the impact of a specific variant and the variable clinical expression of different genotypes. The functional studies of some variants have increased our understanding of the molecular bases of some forms of ADH.